X n nx r r



derivatives of substituted hydrazines.

" A 2,899,432 9 Pat ented Aug. 11,1959.

QUATERNARY PYRAZOLONYL Bernard Rudner, Baltimore, Md., assignor to W. R. Grace & Co., New York, N.Y., a corporation of Connecticut No Drawing. Application January 7, 1957 Serial No. 632,944

11 Claims. (Cl. 260-2475) This invention relates to novel quaternized nitrogen salts. In one specific aspect, it relates to quaterni'zed aspect, it relates to pyrazolonyl hydrazinium compounds.

Heretofore, pyrazolones containing an exocyclic hydrazinium group have been unknown. Although there has been a long history of chemical and medical interest in the pyrazolones and their derivatives, one can easily ascribe the novelty of the compounds of the present invention to the predictable difficulty of their preparation using established prior art methods. It is of course possible to devise paper syntheses of these compounds viapy'razolonyl hydrazine intermediates. Such syntheses cou ld not be considered practical. i 4 "i It has recently been discovered that chloramine will react with tertiary amines to form tri-substituted hydrazinium chlorides. This new reaction presents practically limitless possibilities for the preparation of novel and interesting chemical compounds which because of their structure and inherent physical properties have a wide range of uses. Tertiary amines" are readily available bases. Chloramine is an excellent reagent since it can be economically obtained in commercial quantities by using 11 the well known process of Harry H. Sisler et al., described in US. Patent No. 2,710,248, where chlorine and ammonia are reacted in the vapor phase to produce chloramine"(monochloramine); By treating the pyrazolones and their derivatives with chloramine', I have discovered a new generic class of hydrazinium salts which have remarkable pharmaceutical properties.

It is therefore an object of the present invention to provide a new generic class of hydrazinium salts, useful for pharmaceutical and other purposes, which can be made in commercial quantities. I r

In accordance with the present invention I have discovered a novel and useful generic class of hydrazinium salts corresponding to the general formula:

In the above formula, Ar is selected from the group consisting of phenyl, halophenyl, nitrophenyl, carboxyphenyl and sulfophenyl. R is a member of the group consisting of lower alkyl, sulfoalkyl, hydroxyalkyl, o'r'carbon-constructure having from 5 to 6 endocyclic atoms. K may be taken collectively with R, as indicated, to form a In still another 2 heterocycle. For example, if R=CH CH O and R'=CH CH collectively they form the morpholine structure. R individually is a member selectedffrom the group consisting of lower alkylandhydroxyalkyl radicals. N ranges in value,from 0 to 3. gR" is a member of the group consistingof h'ydrogenf'methyl, ethyl, prop'ylfand allyl radicalsi Rf-f f is a member of the samegroup and may in addition, he C0 --CO H. A can be any. anion.

When my novel compounds are used for pharmaceuticalpurposes it is necessarythat A- be a non-toxic anion, since obviously non-toxicity is )f paramount importance in pharmaceutical work. On the other hand, my new compounds are also useful agents in photo; graphic work. for this purpose the toxicity of the par ticular compoundselected is of little or no importance.

and the solubility properties become of significant interest. In photographic work it is a primary requirement that the particular compound to be selected is water soluble: Such a requirement does not obtain when the new compounds are applied to pharmaceutical or medicinal uses. Other than the solubility or toxicity requirements for specific uses thechoice of anionA: is of little consequence,' since the primaryactivity .of my noveljcornpounds resides in the cation, The salts obtained through the variation of A- may in some cases have special advan tages due to solubility, ease of crystallization, lack of objectionable taste and the like, but these considerations are all subsidiary 'to the characteristics of the cation which are independent of the character of A-. Hence all variations of A- are considered equivalent for the purposes of f"? the present invention. p

A-, in addition'to being a separate electrostatically attached anion, may be an anionic portion of one of the hydrazinium substituents. Specifically, when R or R is a sulfoalkyl radical, the sulfo group contains the-negative charge. Likewise the negative charge is present directly on the hydrazinium structure when R' is CO and Ar is (a hydrazinium betaine).

Specific but nonlimiting examples of the anion A- are as follows: arsenate, orthoborate, bromide, carbonate, chloride, chloraurate, chloroplatinate, chromate, 'dichro mate, cyanate, cyanide, ferricyanide, ferrocyanide, flu o-' borate, fluoride, fluorosilicate, iodide, molybdotungsta'te', nitrate, nitrocobaltate, phosphate, pantothenate, penicilloi ate, phosphomolybdotungstate, silicate, sulfate, sulfamate;

sulfide, thiocyanate, thiosulfate; acetate, benzenesulforiate,"

benzoate, camphorate, citrate, acetylsalicylate, glycollate, gluconate, glucuronate, diliturate, hexafiuorophosphate, hydroxide, lactate, methane sulfonate, abietate, phthalate, -picrate, fumarate, malate, aconitate, itaconate, tricarballylate, tartrate, toluene sulfonate, oleate, stearate,'penicillinate, carbamate, iodomercuriate, gallate, tannate,

"'beniilate, succinate, phenylacetate, oxalate, pyrophosphate, chlorzincate, mandelate, tropate, cinnamate, salicylate, nicotinate, methylenebissalicylate, amphomycin,

sulfanilamide, sulfathiazole, sulfacetimide, sulfasuccidine, .sulfathalidin'e' and the like.

My nova compounds may be readily prepared by the 'siinple reaction sequence shown in Equations 1, 2 and 3.

H O H H O ll||r R a H R W N m I lol o N m 1 N a a 4 A FIIII IIL ma H H m4 a a G N H H P 3 &

N 4 J a. H a o a N a. C c 0 0 N c m m H N m o c o CH0 3 CH C .n L E 3 0 E V N w w m g m n m mm rmm xm amwv W P .m a a o m m m m s.

m H n m N C m h m t .wo c llc a w hm In ll w 0 0 N c sdh o c N c mm N n m N 0y umw W P A m mmm m mw W m M mw m al -e commercially available. Other tertiary amines use- 0 a N m N m C N 4 m m J 4 CH0 5 l v Nrw N ful for the purposes of the present invention arepre- 55 pared from available pyrazolones as shown in Equations 4, 5 and 6, or by other reactions known to those skilled inthe science of preparative chemistry.

s (.14) 1-allyl-5-methyl-4-di-n-propylaminomethyldescribed in my co-pending application S.N. 6Q5, 23 z phenyl 3 pyrazolone filed AuguStZO, 1956, which teaches the reacuon of chlorine and a tertiary amine. in the presence for excess ammonia. For simplicity, when both the base and prod- 0 a 1 5 not are soluble in the same inert solvent, e.g., chloroform, we have formed chloramine in situ by this method in the solution containing the pyraz olone. QR The choicdof solvent-is one ofeco'nomy and sim- NC-CH1 plicity. For good absorption (and therefore reaction) it 10 is desirable to bubble chloramine through a long column of a solution comprising the pyrazolone dissolved in a p I relatively cheap inert solvent. Solvents which serve this purpose include hydrocarbons, e.g., heptane, cyclohexane,

() 1-methy1-4-(2=d1ethylam1n0pr0Py -P Y benzene, Xylene and the like; ethers, e.g., diethyl ether,

s'pyrazolone 15 diamyl ether, dioxane and .anisole; amides, e.g., dimethylformamide and dimethylacetamide; halohydrocarbons,

o CH C H e.g., chloroform, carbontetrachloride, trichlorethylene,

(u: and chlorobenzeney'nitroaromatibs, -e.g.,n1trobenzene.

x-r For special purposes, water andother hydroxylic solvents (32H, such as ethanol and Cellosolvemay be used.

CH The reaction of Equation 1 can obviously only yield the hydrazinium chloride. To provide other useful .T 1 pyrazolonyl hydrazinium salts, it is necessary, by metar thesis, to prepare salts of other anions. The reaction of Equation 2 or a variant is most commonly used for (16) -l,5-diethyl-4-(3-morpholinopropyl)-2-phenylthis purpose. For example, hexafluorophosphates, iodo- 3-pyrazolone mercuriates, stearates and the like can be readily obtained by mixing-aqueous solutionsof the hydrazinium chloride and the appropriate reagent; e.g., hydrazinium chloride and potassium hexafluorophosphate. More often than g C b not, the product hydrazinium hexafiuorophosphate precipitates directly as the reaction progresses. In general, bromides, iodides, thiocyanates, sulfates, fluorosilicates, ferricyanides, bichromates, picrates, picrolonates, dilitu- I T rates, styphnates and 'the like can be obtained with this relative facility. Certain'other salts, e.g., the nitrates, pencillinates, perchlorates and sulfamates, are more water soluble than the chloride at and are therefore not formed under such conditions. Many organic salts, e.g., the benzo-ates, acetylsalicylates, mandelates, and citrates are best made in an aqueous alcohol solution. The nitrates have been readily prepared by mixing alcoholic solutions containing equivalent quantities of silver nitrate In preparing the compounds of the present invention it is usually suitable to contact chloramine with a solution of the basic pyrazolone, allow the reaction to pro- 9 ceed until the desired quantity of chloramine is consumed, and then isolate and purify the resultant hydrazinium chloride by standard laboratory techniques.

While chloraming is most advantageously prepared a and the hydrazinium chloride, filtering off the silver chlo form f h1 fifi m ni d n stream 451 ride which precipitates in quantitative yield and evaporatobtained from a generator constructed according to the ing the Solution to dryness t0 Obtain the hydrazinium teachings of Sisler et 81., other methods are equally nitrate This p ce is also efiicacious in preparing adaptable for the purposes of the present invention. For salts of the pyrazolonyl compounds with acidic antibiotic instance, chloramine can beinade by. reacting chlorine polypeptides such as 'amphomycin. In this case, the with an excess of ammonia in carbon, tetrachloride solualkali metal salts of the antibiotic can be used in place tion or similar halogenated hydrocarbon solvent under of silver salts. Salts of other medicinals, e.g., the acidic controlled conditions of mixing at low temperatures. sulfanilamide derivatives can be made in either aqueous Such a procedure is fully described in US. Patent No. or anhydrous solutions as shown in Equation 7:

i C-C-CHr-N i -c-ong NE: on,

o A i-C-JhHp-N AQN/ H [NQNQBOzNOOCHs] NaCl \N- -on, NB,

2,678,258, 'to John F. Haller. Another efiective pro- When a highly insoluble salt is to be formed from the edure is that of Coleman et al. fully described in Inanion of a relatively water-soluble acid, the acid itself organic Syntheses, vo'l. 1,59 (1939). Alternatively, the may be used to furnish the anion. Thus adding satuchloramine can beformed in the presence of the amine as rated aqueous solutions of phthalic acid even to dilute solutions of many of the hydrazinium chlorides gives a sometimes. slow, but always quantitative, precipitate of the "hydrazinium phthalate. Many oxalates and picrates have been prepared by this method. The salts obtained by these, or other methods, are generally crystalline solids, depending largely on the nature of the anion. Bulky organic anions, e.g., stearate, oleate, abietate, etc., tend to yield waxy or pasty products. Bulky inorganic anions such as phosphotungstomolybdates and ferricyanides tend to yield amorphous powders of very high decomposition points. Salt derived from simpler organic and inorganic anions which are in themselves very soluble, e.g., succinate, citrate, tartrate, gluconate, acetate, and nitrate tend to be relatively low-melting (70-150 C.), water-soluble, and sometimes hygroscopic. The hyd'raz'inium hydroxides, best prepared by the action of freshly precipitated Ag O on the hydrazinium chlorides (see Equation 3) arevery hygroscopic and diflicult to isolate. They show a marked tendency to react with atmospheric acids such as CO: (Equation 8).

My invention is further illustrated but not delimited by the following specific examples:

Example I A chloramine generator was constructed according to the teachings of Sisler et al., supra. The generator consists o f -a horizontal Erlenmeyer flask, the bottom 'of which contains an outlet tube which is directed into the reactor containing liquid tertiary amine. Ammonia and chlorine (which may be diluted with nitrogen) are in troduced separately into the top of the flask through concentric conduits. Chloramine and ammonium chloride are formed in the flask at the point where the chlorine and ammonia vapors come into contact. A red is provided in the chlorine inlet stream to prevent any plugging of that stream with ammonium chloride. The outlet end of the flask is masked with glass wool to collect any ammonium chloride particles which otherwise would be directed into the bath of the amine. The chloramine yield for any one set of gas flow meter readings is determined by removing the reactor and generating the chloramine directly into a series of three chilled traps. Under the conditions of chloramine generation, only ammonia, chloramine, and nitrogen can pass through the glass wool into the traps. Since the traps are maintained at at least 70 C., the ammonia and chloramine condense therein and react relatively slow (compared to the chlorine-ammonia reaction velocity) tojorm nitrogen and ammonium chloride. By allowing the low temperature condensate to come to .room temperature slowly, the chloramine is' converted quantitatively to non-volatile (at 20-30" C.) ammonium chloride, while the ammonia and nitrogen escape by volatilizationn Therefore titration of the white residue (obtained on evaporation of the condensate) for chloride gives a direct measure of the chloramine generated. This can be related back toa measure ot the chlorine used to obtain the chloramine yield.

There is an alternate procedure which is suitable for use when chloramine is actually being consumed by reaction with a tertiary amine. The amount of chlorine used in a run, which is the limiting reagent quantity for yield calculation, can be measured directly, e.g., by weight of the chlorine cylinder before and after use, or by use of flow meters. The amount of ammonium chloride retained within the generator is determinable by titrating an aliquot of the aqueous solution of all of the solid remaining within the chloramine generator after the reaction has been completed. The chloramine yield, expressed as percent of the theoretical yield, can then be calculated from the formula:

where A is the total number of moles of chlorine passed into the generator and B is the number of equivalents of chloride retained within the generator. The chloride content of the generator thus serves as an indicator of chloramine efliciency.

. Example 11 A solution of 20.2 g. of 1,5-dimethyl-4-dimethylamino- 2-phenyl-3-pyrazolone, commercially available as Pyramidon or Aminopyrine was completely dissolved in 100 ml. of xylene, and treated with the chloramine from the generator described in Example I. The chloramine treatment continued for about minutes using in all about one-tenth mole of chloramine. Of this, approximately half escaped without reaction because of insuflicient contact time obtained in the 3-necked flask. The reaction was slow and slightly exothermic; the temperature rose from 32-37 C. After gasification, the reaction mixture became red-brown. It contained some solid and also some active chloride determined by the standard potas sium iodide-acetic acid test. The mixture was allowed to stand overnight by which time all of the active chloride had disappeared. It was filtered and the residue was washed with three ml. portions of C H The filtrate and the washings were combined and evaporated to dryness. The residue thus obtained was 6.5 g. of a redbrown solid which by analysis was 86% pure, 1.1-dimethyl 1-(1,S-dimethyl-Z-phenyl-3-pyrazolonyl-4)hydrazinium chloride. Alternatively, this compound can be named, 1,l-dimethyl-l-(antipyrinyl-4)hydrazinium chloride. The novel product darkened at 144 C. and melted with decomposition at 147 C. The yield corresponded to approximately 50% chloramine conversion. The crude product was dissolved in cold isopropyl alcohol, filtered free of ammonium chloride and evaporated dry to give a dark red syrup which was water soluble. Vacuum evaporation convertedthe syrup to dark red rhombic crystals which were wet with oil. These were nuchared in water, then precipitated from isopropyl alcohol solution with diethyl ether to give off-white clusters of prisms melting at 153 C. and above with decomposition. The purified product was soluble in water, methyl alcohol, ethyl alcohol, isopropyl alcohol, Cellosolve and chloroform; insoluble in ethyl acetate, diethyl ether and xylene.

The preparative reaction of this novel compound is shown below in Equation 9:

11 E amp e III An aqueous solution of the product of Example II was treated with aqueous potassium hexafluorophosphate to give 'the corresponding hydrazinium hexafluorophosphate. The crudeproduct melted at 174176 C. After recrystallization from absolute ethanol the melting point obtained was 180 C. i

The dull yellow picrate was formed upon treatment of aqueous hydrazinium chloride with saturated aqueous picric acid solution. This novel product decomposed at about 182 C. r 7

An immediate yellow precipitate was obtained by treating the hydrazinium chloride with aqueous potassium mercuri-iodide. This precipitate, the hydrazinium iodomercuriate, became dark brown in air. It melted at 73-74 C. to give and liquid.

Example 1V An aqueous solution of the product of Example II, 1 g. in ml. of water at'pH 7.5-8.0, was treated with a saturated aqueous solution of calcium acetoxybenzoate (1.5 g). The mixture was allowed to stand overnight. From it was obtained a 78% yield of 1,1-dimethyl-1- (antipyrinyl-4)hydrazinium Z-acetoxybenzoate, as long needles which melted from 145147 C. It was recrystallized from water as fine needles melting at 149149.5 C. The preparative reaction is shown in Equation 10 below.

The procedure of Example II was substantially re peated; however, the 3-necked flask used as the reactor was replaced with a modified Fisher'Milligan gas absprption bottle. Using the modified apparatus, the chloramine gas instead of bubbling through approximately two inches of aminopyrine solution, bubbled through a head of approximately 35 inches. The result was a near quantitative absorption of chloramine in an 86% conversion to light brown 1,l-dimethyl-l-(antipyrinyl-4-)hydrazinium chloride. The crude product melted between 142-145 C. It contained appreciably less ammonium chloride than the crude product of Example II. It was extracted with chloroform and the yellow ammonium chloride-free solution was evaporated at room temperature to give a yellow oil which on trituration with acetone gave otT-white fine prisms melting at 152 C. with decomposition. Recrystallization from a chloroformxylene mixture did not change the melting point, which is markedly dependent on the rate of heating.

Example VI The procedure of Example IV was substantially repeated by treating the product of Example V with sodium salicylate. The resulting product was fine white prisms of hydrazinium salicylate melting at 187-1885 C.

12 Example VII Methyl alcohol solutions of potassium penicillin G and antipyrinyl dimethyl hydrazinium chloride, were mixed and evaporated to dryness in a nitrogen stream. The reaction mixture was taken up in chloroform, charcoaled, filtered, reevaporated to dryness in the absence of air, redissolved in chloroform, and the process repeated, The product was finally precipitated from an acetone solution by the addition of excess peroxide-free ether, and appeared a clear, tacky gum of the penicillin salt, which could not be crystallized by vacuum-drying, triturartion, or chilling. It ran clear at 55 C and decomposed with gas evolution at 65 It was readily soluble in chloroform (potassium penicillin G is not) acetone (the hydrazinium, chloride is not) and alcohol, but only slightlyfsoluble. in ,cold water '(both reactants are highly water soluble). t 1 l i i Example VIII The product of Example .V was treated with calcium amphomycin, the calcium salt of an antibiotic, acidic polypeptide. The reaction mixture was allowed to stand overnight and a reddish salt decomposing at about 185 C. was obtained therefrom.

Example IX A large quantity of morpholine hydrochloride was prepared by saturating a cold dry diethyl ether solution of morpholine with dry H01, filtering out of contact with air and vacuum drying in a desiccator over sulfuric acid. 22.58 g. of antipyrine (0.12 moles) was mixed with 14.83 g. (0.12 mole) of morpholine hydrochloride. The mixture was treated with 10 g. of formalin (equivalent to 3.6 g. or 0.12 mol formaldehyde). Within ten minutes after the mixing most of the solid had dissolved. The resulting light yellow solution increased in temperature from 28 to 45 C. by the heat ofthe reaction. On standing overnight, the solution gelled because of product precipitation. After the addition of an excess of 20% sodium hydroxide solution, the product was filtered and was washed with a little water (in which it is soluble), The air dried crude 1,5-dimethyl-4-(morpholino-44 methyl)-2-pheny1-3-pyrazolone, melting point of 129- 130 C. (literature value 131 C., see Chemical Abstracts 13, 2511), was obtained therefrom in quantita-. tive yield. This preparation is shown in Equation 11 hereunder.

Example X 9.78 (.12 m) dimethylamine hydrochloride. The re 13 .14 p ractio'n was les'sfexothfermic than that of Example IX and was treated with 1.5 g.'of formaldehyde'( 4.3 g1 formaliri) less complete after 2 4'hours. The reaction mixture was and 9.51 g. (.05 mole) antipyrine. An exorthermic retherefore allowed to stand for 48 hours. The viscous action ensued and within 1 minute a gel was formed. clear reaction mixture was diluted with water and treated Water was added to the mixture to dissolve the gel. 'with excess sodium hydroxide, extracted with three 40 ml. '5 'Using awork-up procedure similar to that described in portions of chloroform and evaporated infair. It gave "Example X, a'quantitative yield of N,N-bis(l,5-dimethyl- 79.9% of theory of crude 1,5-dimethyl-4-dimethyl- 2-phenyl-3-pyrazolonyl-4-)methylpiperazine was obtained aminomethyl-Z-phenyl-B-pyrazolone. See preparative therefrom. See Equation below.

fl utwzs wh a d 1 *ExamplXW 1 5(12 'jF-(IIIYP "j .1 r I 2.0 The generator of Examplelwas adjusted to permit'the C-C-H reaction of a gaseous chlorme-mtrogen stream with ammonia at flow rates of 0.065 mole, 0.018 mole, and 0.350 mole per minute respectively. Under these operating con- ..ditions the yield of chloramineobtained was 87% of 011.25

. p N/ g. of the product of Example X were completely disi solved in chloroform and subjected to chloramine-am- 0H; monia stream from the generator for a period. of 3 minutes. The mixturejwas allowed to stand overnight, 30 after which time it gave a negative response to the active H20 chloride tests. It was filtered and 4 g. of air-dried residue I Example X1 were obtained therefrom. Evaporation of the combined filtrate and wash gave 27 g. moreof crude brown 1,l-di- Procedure of the two precedmg examples was methyl-l-antipyrinyl-4-)methyl hydrazinium chloride desubstantially repeated using 12.9 g. of pyrrolidine hy- .dro Using the workup technique similar to composing 148-151 C. Thls product was extracted with that described in Example X, a quantitative yield of crude cold alcohol a filtered free of P P 1,5 -.dimethyl-4-pyrrolidinomethyl-2-phenyl-3-pyrazolone chlorldewas then evflporilted t dryness in an obtained therefrom. See Equation-13 stream to give a dark red 01]. WhlCh, under vacuum, largely solidified. The product was soluble in water, chloroform,

" i g f: 40 .methyl alcohol and isopropyl alcohol; it was insoluble in f o carbon tetrachloride, diethyl ether, dimethyl ketone, ethyl QN ll 2 N acetate and dioxane. It was purified by precipitation from concentrated chloroform solution by acetone. The

preparative reaction is shown in Equation 16 below: 7

o-c-om-N Q (16) cm cm 1 i t 6 p I em onfriHf- +1110 .1 it i 7 Example XII i 011- v The procedure of the preceding examples was substantially repeated using 14.6 piperidine hydrochloride. 0 OH; I. The-resulting product was 32.5 g. of LS-dimethyll- 1 lj. piperidiriomethyl-2-phenyl-3:pyrazolone. ,The yield there 1 by obtainedrepresented 95% of theoryr See Equation li4below. N- -on.

(LG-H r H +9380 T Usingalternativenomenclature to that indicated aforei m-the product could be named 1,1-dimethyl-1-(1,5-dif p 1' r a methyl-2-phenyl-3-pyrazolonyl-4-)methyl hydrazinium v g Y chloride. It softens, under very slight pressure, at about room temperature, melts clear at about 55 C.,'and dark- N\ C1 ens and decomposes with gas evolution from about 100 5 C. on. Its picrate is a dull yellow, air-oxidizable gum. i H: Its hexafluorophosphate, amorphous and unstable, de-

+1110 composes indefinitely beginning at about 143 C. The t Example XIII citrate, benzoate,mandelate, sulfate, and nitrate are highly (0.025 mole) of piperazine dihydrochloride hygroscopic and intractable gums. The iodide, yellowish brown, relatively water-soluble, decomposes with darkening from about 162 C.'on.' I. l.

Example XV Using a procedure similar to that of Example XIV the product of Example XI, dimethylpyrrolidinomethylphen- The product was extracted with chloroform, and precipitated from this solution by addition of acetone. .It was purified by repeated precipitations from charcoaled solutions in chloroform and alcohol by addition of acetone .or xylene. Vacuum drying the gum thus obtained gave a tacky, hygroscopic brown gurn which had very nearly the correct chloride analysis (calculated 11%,.found 10.4%). Repetition of this partitioning procedure several times finally gave an oil-white, amorphous solid, the amino pyrrolidinium chloride, which melted and decomposed at about 128 C. The dull yellow picrate darkened at about 107 C., and melted to a black tar at abount 131 C. The amorphous yellow hexafluorophosphate decomposed at approximately 152 C. The citrate, benzoate, phthalate and mandelate were hygroscopic gums. The nitrate, which melted at slightly above room temperature, was highly hygroscopic and air sensitive. Its salt with sodium groscopic solid melting clear at about' 125- 130" C. lls

preparative reaction is shown in Equation 1 l i NH:

N C H (5H; Ha Its picrate (decomposing at about 137 C.), hexafluorophosphate (melting point about 132133.5 .C. with gas evolution) and sulfacetimide salt (d. about 179 C.) are water-insoluble, while the sulfate (d. 206-209" C.) and acid succinate (deliquescent) are water-soluble.

Example XVII The product of Example XII was treated in a manner similar to that described in the previous examples. After chloramination, a precipitate was obtained from the reaction mixture weighing 37 g. It contained 20.9% chloride ion, equivalent to about an 80:20 mixture of 1 amino 1 (1,5 dimethyl 2 phenyl-3-pyrazolonyl- 4-)methylpiperidinium chloride and ammonium chloride. Purification by recrystallization from ethanol-acetone mixtures gave soft, hygroscopic crystals, melting with decomposition at about 142C. With appropriate treatment the product gave a picrate, very fine canary yellow needles, d. 170 C., and a hexafluorophosphate, fine white rods, melting point 174175 C., with preliminary darkening. Its salts with sulfapyridine and sulfathiazole'were uncrystallizable oils. Although it failed to yield a waterinsoluble salt with penicillin G, it formed slowy theicorresponding penicilloate, d. 187-191 C. Very slow evaporation of the mixed aqueous solutions of the reactants gave the amphomycin salt as a somewhat water-soluble, voluminous white powder, which decomposed indefinitely above 200 C.

Example X VIII sulfathiazole, formed in aqueous solution according to Equation 18. 10 g. of the product of Example XIII were dissolved in ll NH: NaCl+ EgCH:

This novel salt shows loss of water at about98'C., and a large excess of chloroform and treated with the chlordecomposes at about 145 C.

Example. XVI I The procedure of Example XIV was substantially repeated using as a reactant the product of Example IX. After the chloramination was complete, a 29 g. residue of crude reddish brown 4-amino-4-(1,5-dimethyl-2-phenyl-3-pyrazonoyl-4-)methylmorpholinium chloride was obtained in admixture with ammonium chloride in approxiamine-ammonia gas stream from the generator for 15 minutes. The reaction mixture was filtered to give 5 g. of solid containing about 60% ammonium chloride and 40% crude 1-amino-1,4-bis-(1,5-dimethyl-2-pl1eny1-3- pyrazolonyl-4-)methylpiperazinium chloride. Evaporation of the combined filtrate and wash gave 7 g. of a tan crude product, pure piperazinium chloride, which, after recrystallization, decomposed and melted at 206-208 C. From the recrystallization motherliquors was obtained mately 80-20 proportions. The novel product was a hyslightly more, one-tenth of a gram of an additional I organic salt 1 (B .in Equation 20 below) decomposing at ,about-260 C., which I believe to be l,4-diamino-,1,4-bis- (1,5-.dimethy1 -.-2 -.phenyl --3 pyrazolonyl 4 methyl) .piperazinium dichloride. .Its hexafluorophosphate deriva- Example XIX 20 g. of. 1,5 dimethyl-2-phenyh4-(N-methyl N-sulfo- .methyDamino-S-pyrazolone, available commercially as *Novalgirf *or' Dipyrone', were dissolved in 50 ml. of water. "-of 2.1- equ-ivalents of chloramine' from the generator over This aqueous'solution was treated with a total l8 7 Example XX Twenty percent solutions (if such was not possible,-

saturated aqueous solutions) of potassium permanganate, potassium ferrocyanide, sodium sulfocyanate, potassium tive decomposed-without clear-cutmeltingat about 212 The mono Chloramine adduct A in Equation 0 mercun-iodide, sodium dichromate, ferric chloride, gave an amorphous, l yellow picrate h d k d potassium iodide, sodium citrate, sodium gluconate, sodiand melt d at 164-165 C, d a f i tl i k, i um acetate, sodium sulfathiazole, sodium diethyldithiocrystalline hexafluorophosphate that meltedwith decomcarbamate and S-nitrob'arbituric acid were prepared. position .atr'3Tl-55 ..C. I I 10 These solutions were mixed withone-fourth their volume of 5% aqueous solution of the chloramine adducts of aminopyrine (the product of Example II) 1,5-dimethyl- 2-phenyl-4-piperidinomethyl-3-pyrazolone (the product of Example XVII), and Dip yrone (the product of Example XIX). The results obtainedthereby are shown in Table 2 below:

TABLE 2.-HYDRAZINIU M CHLORIDE PRODUCT Reagent Example II Example XVII Example XIX flFeOla e purple solution, fading quickly no change -b1ue solution which turned gr 9611- KMnOi very rapId reduction no precipitate, slow reduction. 5 immediate reduction. K Fe(CN)a translent greener so1ution..-.. no precipitate no change, KHgI gummy yellow precipitatewhite precipitate un ab Do. I slow yellow precipitate no precipitate Do. NaSCN no change do; Do. Na2G1'zO7 slow yellow-brown precipitate. do Do. Sodium citrate. no change do Do. Sodium glucona do d Do. Sodium acetate do Do. Sodiumsulfathiazole -do do Do, 'Sodium diethyldithioearbamate. slow-precipitate, do H. Do. 5-nitrobartituric acid precip1tate;d. 200 yellow precipitate, d. 200. yel1ow precipitate,*d: 200.

a period of about 82;:minutes. The resulting cherry red solution was evaporated to dryness to give 28 g. of crude l-methyl-1-sulfomethyl-l-(1.,5-dimethylr2-phenyl-3- pyrazolonyl4-)hydrazinium betaine (see Equation 21 below). The tan, slightly hygroscopic solid, part of which darkened and melted. at l60163 C., was purified by .washing with alcohol sullfomethyl hydrazinium chloride.

0 CH3 Y o l H ClNHsa 'white, deliquescent amorphous solid,"presumably the" Example XXI 0.3 g. of the product of Example II were dissolved in 5' ml. of deionized water and. treated with an equivalent of silver-nitrate as a 0.1 N aqueous solution. An excess of two drops of silver nitrate solution were added thereto. The resulting reaction. mixture was filtered and washed well with deionized water. The filtrate Wasconcentrated in vacuo :togive. 0.31 g. of vacuum dried, hygroscopic .tan. crystals. The hydrazinium nitrate thus obtained melts :in water at slightly above room temperature at atmospheric pressure. It decomposes attabout C. The

preparative reaction is shown hereunder in Equation 22.

Example XXII 0.25 g. ofthe product of Example XV were dissolved in 10 ml. of water and treated with 0.55 equivalent of silver sulfate as-a saturatediaqueoussolution. The mixture was allowed to stand for two hours and thereafter filtered and washed well with cold water until the wash in threeSO ml. portions and each time allowed to stand yield of the hydrazinium sulfate which melted with de- 2,899,432 .19 20 liquorwas free of silver ions. The resulting mass was septracted in nitrogen-saturated isopropyl alcohol using three arately slurried with ammonium hydroxide solution 30 ml. portions. Evaporation of the extractfollowed by vacuum drying, gave a 52% yieldofonce recrystallized 5 minutes before filtration- The material was finallyv 1,l-dirnethyl-l-(antipyrinyl-4-)hydrazinium penicillin G washed once with water and vacuum dried to give a low salt. This novel product decomposed above 150 C. The

preparative reaction is shown below in Equation 25.

) 0.001 mole of sodium barbital U.s.P. was refluxed in 0 v v I 100 ml. of absolute ethanol for minutes. The resulting tsolution was filtered hot into 100 ml. of an absolute 2 Q NH1 01. Agzso ethanol solution containing 0.01 mole of the product of l I 1 Example II. This mixture was refluxed for an additional 13, two hours. It was filtered hot, allowed to cool and refil- 0 tered. Thefiltration residue contained sodium chloride and a small amount of the product. The filtrate was evaporated dryin a nitrogen stream, then recrystallized with decolorization from an isopropyl alcohol-ethyl. acetate mixture to give a 72% yield of 1,1-dimethyl-1-antipyrinyl- CH: CHl' 2 hydrazinium 5,5-diethylbarbiturate, decomposing above P 'XXlII 184 C. The preparative reaction is shown below in 0.01 mole each of the product of Example X and cal-- 5 Eq Jee zAgcr CH; 0 Na 0 OHa JHs 311: E (ilHa (i'iHa cium gluconate were suspended in ml. of 95% ethanol My novel salts have remarkable properties which and refluxed for three hours. The mixture was filtered make them especially useful as pharmaceuticals, agents and the hot filtrate evaporated dry. The substance there- 50 for photographic work, and dyestulfs. Perhaps the most by obtained was washed well with ethyl ether to remove important use for these new compounds is as pharmacalcium chloride, and with chloroform to remove any ceutical ingredients. Almost since the time that Knorr excess of the produce of Example X. It was then recrysfirst prepared antipyrine, the effectiveness of this type of tallized from isopropyl alcohol and ethyl acetate to give compound as an antipyretic analgetic has been demona low yield of frangible, hygroscopic white lumps which strated. My novel products maintain these remarkable decomposed indefinitely at about 200 C. The prepara properties as well as possessing the additional antispastive reaction is shown in Equation 24. modic action characteristics of the quaternized nitrogen (H) CH: q C

Example XXIV compounds. In comparison with the salts of aminopyrine A Solution containing 0001 mole of the product of and antipyrine, my novel salts, e.g., the nitrate, chloride,

Example H, a like amount of potassium pencmin G in 7 acetate and the bite are frequently more water-soluble 50 ml of water and approximately 10 of hydro and the aqueous solutions thereof are invariably more quinone was evaporated dry at 1015 C. using a stream clearly neutral and much more Stable to alkali- TWO of deoxygenated nitrogen as the vapor carrier. The ligh specific illustrations will demonstrate these desirable properties.

tan residue was washed with ethyl ether to remove the hydroquinone (in a nitrogen atmosphere) and then ex- First, aminopyrine hydrochloride is a deliquescent solid which is freely soluble in water. The aqueous solutions have a strongly acid reaction. The product of Example II is a non-deliquescing white solid which is freely soluble in water; its aqueous solutions have a pH of about 6.5 (just about neutral). Treatment of a antipyrine hydrochloride solution with a relatively weak base such as ammonium hydroxide causes precipitation of free aminopyrine. Treatment of the corresponding hydrazinium salt in water with ammonium hydroxide produces no effect; from the clear solution the aminopyrine hydrazinium salt can be recovered quantitatively, e.g., by evaporation.

Second, aminopyrine forms compounds with barbiturates which have been recommended as analgesic-sedatives. These hot-water-soluble, cold water-insoluble products, on being treated with a cold aqueous sodium carbonate or hydrochloric acid are split into their components. Such a hydrolysis is noticeable even in the presence of inorganic salts alone. The barbital salt of the hydrazinium compounds, however, are not hydrolyzed by cold bases, salts or acids.

This desirable resistance to simple hydrolysis makes our products valuable ingredients of medicinal mixtures, e.g., in analgesic sedative formulations containing a barbiturate. In such cases, it is often unnecessary, and therefore undesirable, to prepare beforehand the barbiturate hydrazinium salt, since simple dry mixing of its two progenitors effectively gives the product.

Some of my novel salts have amazlng powers as microbial agents. When tested by the Oxford cup technique, the acetylsalicylate hydrazinium salt of aminopyrine was approximately as effective against nutrient agar colonies of P. aeruginosa, S. marescens, and E. coli as a comparable concentration (0.01%) of phenol or Zephiran. It was more efiective than phenol against Ch. globosum (potato agar colonies) at 0.01% concentrations.

My novel products are also useful as chemical intermediates. Two examples will sufiice to establish this:

First, active aldehydes, e.g., chloral and formaldehyde, condense readily with the hydrazinium compounds to form crystalline derivatives. With chloral, chloral hydrate, chloral alcoholate, butyl chloral or its hydrate, the products are useful analgetic-sedatives, similar to the commercially available Trigemin but appreciably more water-soluble. With formaldehyde, condensates having two hydrazinium moieties connected by a methylene group can be obtained. These have shown some value as special anti-oxidants.

Second, I have found that diazonium salts react with these hydrazinium compounds according to the reaction:

These novel products are analogous to the commercially important stabilized diazo compounds available under such trade names as Levamine.

My novel pyrazolonyl hydrazinium salts are, under certain conditions, unexpectedly efiective antioxidants and reducing agents. This is true of the salts in general, e.g., chlorides, thiocyanates, sulfates and acetates, but the utility of the compounds varies somewhat with the nature of the anion. Thus the ascorbates, sorbates, and glutaconates-salts of unsaturated lower alkyl acidsare marked reducing agents, rather than anti-oxidants. The halides, for example are primarily anti-oxidants rather than reductants. They are, for example, relatively stable to many common oxidants in an acidic atmosphere, but in alkaline media, they react readily with oxidizing agents. This inherently characteristic chemical property is valuable in many fields, for example, photography. Both hydrazine and pyrazolone derivatives are known to be of value in photographic development (see Mees, Theory of the Photographic Process, pages 535-619, 1038-9). The hydrozines would be far more useful in this work, however, if the effective, cheaper ones were more water-soluble and less toxic (see Kirby, US. Patent No. 2,220,929 (1940)). The heterocycles also suffer the disadvantage of insuflicient water solubility. I have found that my novel products, derivatives of both the pyrazolones and the aryl hydrozines, are highly water-soluble developers capable of controlled reduction of the silver halide in a photographic film.

I claim:

1. Compounds according to claim 9 wherein R and R are lower alkyl, and n equals 0.

2. Compounds according to claim 9 wherein R and R are lower alkyl, and n equals 1.

3. Compounds according to claim 9 wherein R is sulfoalkyl, R is lower alkyl, and n is 0.

4. l,1-dimethyl-l-(1,5-dimethyl-2-phenyl 3 pyrazolonyl-4)-hydrazinium Z-acetoxybenzoate.

5. 1,1-dimethyl 1 (1,5-dimethyl-2-phenyl-3-pyrazolonyl-4)-methylhydrazinium chloride.

6. 4-amino 4 (l,5-dimethyl-2-phenyl-3-pyrazonyl- 4) -methylmorpholinium chloride.

7. l-amino 1 (1,5-dimethyl-2-phenyl-3-pyrazolonyl- 4)-methylpiperidinium chloride.

8. l-methyl 1 sulfomethyl-l-(1,5-dimethyl-2-phenyl- 3-pyrazolonyl-4)-hydrazinium betaine.

9. New chemical compounds having the general formula:

( JHa wherein R, taken alone, is a member selected from the group consisting of lower alkyl, hydroxy lower alkyl and sulfoalkyl; R, taken alone, is a member selected from the group consisting of lower alkyl and hydroxy lower alkyl; R and R, taken together with the N on which they are both substituents, form a non-aromatic n'ng selected from the group consisting of morpholine, piperidine, piperazine and pyrrolidine; n has the values of 3, 2, 1 and 0; and A is a pharmaceutically acceptable anion.

10. Compounds according to claim 9 wherein R and R' taken together with the N on which they are both substituents form the morpholine ring and n equals 1.

11. Compounds according to claim 9 wherein R and R' taken together with the N on which they are both substituents form the piperidine ring and n equals 1.

References Cited in the file of this patent Omietanski et al.: I. Am. Chem. Soc., vol. 78, p. 1211 et seq., January-March 1956.

UNITED STATES PATENT OFFICE Certificate of orrection Patent No. 2,899,432 August 11, 1959 Bernard Rudner It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Columns 3 and 4;, the equation shown between lines 61 and 7 2 should be numbered -(6) at line 61; columns 7 and 8, lines 56 to 68, left of the equation insert (7) at line 56; same equation (7), line 66, for N N read H N; column 12, line 14, for 65. read -65 C.; column 13, lines 10 to 15, left-hand portion of Equation (15) should appear as shown below instead of as in the patent Signed and sealed this 1st day of March 1960.

Attest: KARL H. AXLINE, ROBERT C. WATSON, Attesting Officer. Commissioner of Patents.

UNITED STATES PATENT OFFICE Certificate of (Jorrection Patent No. 2,899,432 August 11, 1959 Bernard Rudner It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Columns 3 and A, the equation shown between lines 61 and 7 2 should be numbered (6) at line 61; columns 7 and 8, lines 56 to 68, left of the equation insert -(7) at line 56; same equation (7), line 66, for N 1. read H N-; column 12, line 1%, for 65. read 65 (1-; column 13, lines 10 to 15, left-hand portion of Equation (15) should appear as shown below instead of as in the patent- Signed and sealed this 1st day of March 1960.

[SEAL] Attest: KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Ofit'oer. Commissioner of Patents. 

6. 4-AMINO- 4 - (1,5 - DIMETHYL-2-PHENYL-3-PYRAZONOYL4)-METHYLMORPHOLINIUM CHLORIDE.
 9. NEW CHEMICAL COMPOUNDS HAVING THE GENERAL FORMULA: 